Efinaconazole, chemically designated (2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol, also known as Jublia or KP-103, is the first triazol compound approved for a topical medication for onychomycosis.
Several patents and patent Publications (U.S. Pat. No. 5,716,969, WO 94/26734, US 2013/150586, WO 2005/115398, JP 10212287 and EP1693358); and scientific publications (Konosu, T. et al. Chem. Pharm. Bull, 1991, 39(9), 2241; Tasaka, A. et al. Chem. Pharm. Bull., 1993, 41 (6), 1035; Konosu, T. et al. Tetrahedron Lett., 1991, 32(51), 7545; Bennett, F. et al. SYNLETT, 1995, 1110; Acetti, D. et al. Tetrahedron: Asymmetry 2009, 20, 2413; and Pesti, J. et al. Org. Process Res. Dev. 2009, 13, 716) disclose processes for the preparation of Efinaconazole by interaction of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]-oxirane (“epoxytriazole”) with 4-methylenepiperidine. Also disclosed are Efinaconazole intermediates and building blocks.
Since Efinaconazole contains two adjacent chiral centers, the synthesis of enantiomerically pure compound is complex and thus far, all the known syntheses are not efficient enough and do not enable a cost effective manufacturing procedure on a commercial scale.
U.S. Pat. No. 5,648,372 and U.S. Pat. No. 5,792,781 describe enantioselective synthesis of compounds related to Efinaconazole from chiral 3-hydroxy-2-methyl propionic acid in 12 steps with an overall yield lower than 5%. In another approach comprised of 13 steps and low overall yield, (R)-lactic acid was used as the starting material (Tsuruoka, A. et al. Chem. Pharm. Bull. 1998, 46(4), 623 and Kaku, Y. et al., ibid. 1998, 46(7), 1125). Because both starting materials contain only one chiral center, the second, adjacent chiral center has to be created by a diastereoselective reaction (using either Corey or Sharpless epoxidation method). However, this reaction is not sufficiently selective leading mostly to a mixture of two diastereomers which have to be separated. The second approach, for synthesis of (“epoxytriazole”) based on (R)-methyl lactate, was optimized on a multi kilogram scale (Pesti, J. et al. Org. Process Res. Dev., 2009, 13, 716), but still involves 8 manufacturing steps (scheme 1), with an overall yield of 16%, which is not cost effective for commercial scale production:

Another approach, using catalytic asymmetric cyanosilylation of 2-chloro-1-(2,4-difluorophenyl) ethanone (2′) was described (Tamura, K. et al., J. Org. Chem., 2014, 79, 3272), claiming the shortest method reported to date for Efinaconazole synthesis. The method comprises 7 steps, in which four steps have performed as two “one-pot” synthesis:

However, the procedure has several potential drawbacks as a method for large-scale synthesis. Aside from the use of the non-commercially-available sugar-derived chiral ligand, the use of gadolinium bis(trimethylsilyl)amide is problematic: it is corrosive, reacts vigorously with water, and should be manipulated with air-free technique in extra dry solvents. In addition, the process is conducted in cryogenic conditions (T=−78° C.), which requires special equipment and employs microwave irradiation, a technique typically used in laboratory scale, with limited industrial applicability.
Another disadvantage of the aforementioned process is the use of hazardous materials such as diisobutylaluminium hydride (DIBAL), a combustible reagent which reacts violently with air and water. In addition, the use of DIBAL leads to poor atom economy of the reaction, yielding voluminous aluminum salts, which have to be separated from the product and disposed of. The cost of such hazardous material disposal is considerable.
Therefore, there continues to be a need in the art for a practical method for making Efinaconazole, which not only avoids the problems of the existing art, but is also safe, cost effective, and industrially feasible.